Melbourne Medical School Collected Works - Research Publications

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    Associations between symptoms and functional capacity in patients after COVID-19 infection and community controls
    Huynh, Q ; Wexler, N ; Smith, J ; Wright, L ; Ho, F ; Allwood, R ; Sata, Y ; Manca, S ; Howden, E ; Marwick, TH (WILEY, 2023-09)
    BACKGROUND: Post-acute sequelae of COVID-19 (PASC or 'long COVID') reflect ongoing symptoms, but these are non-specific and common in the wider community. Few reports of PASC have been compared with a control group. AIMS: To compare symptoms and objective impairment of functional capacity in patients with previous COVID-19 infection with uninfected community controls. METHODS: In this community-based, cross-sectional study of functional capacity, 562 patients from Western Melbourne who had recovered from COVID-19 infections in 2021 and 2022 were compared with controls from the same community and tested for functional capacity pre-COVID-19. Functional impairment (<85% of the predicted response) was assessed using the Duke Activity Status Index (DASI) and 6-min walk distance (6MWD) test. A subgroup underwent cardiopulmonary exercise testing before and after exercise training. RESULTS: Of 562 respondents (age 54 ± 12 years, 69% women), 389 were symptomatic. Functional impairment (<85% predicted metabolic equivalent of tasks) was documented by DASI in 149 participants (27%), and abnormal 6MWD (<85% predicted) was observed in 14% of the symptomatic participants. Despite fewer risk factors and younger age, patients with COVID-19 had lower functional capacity by 6MWD (P < 0.001) and more depression (P < 0.001) than controls. In a pilot group of seven participants (age 58 ± 12 years, two women, VO2 18.9 ± 5.7 mL/kg/min), repeat testing after exercise training showed a 20% increase in peak workload. CONCLUSIONS: Although most participants (69%) had symptoms consistent with long COVID, significant subjective functional impairment was documented in 27% and objective functional impairment in 14%. An exercise training programme might be beneficial for appropriately selected patients.
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    Digital Health Programs to Reduce Readmissions in Coronary Artery Disease
    Braver, J ; Marwick, TH ; Oldenburg, B ; Issaka, A ; Carrington, MJ (Elsevier BV, 2023-10)
    BACKGROUND: The use of mobile health (mHealth, wireless communication devices, and/or software technologies) in health care delivery has increased rapidly in recent years. Their integration into disease management programs (DMPs) has tremendous potential to improve outcomes for patients with coronary artery disease (CAD), yet a more robust evaluation of the evidence is required. OBJECTIVES: The purpose of this study was to undertake a systematic review and meta-analysis of mHealth-enabled DMPs to determine their effectiveness in reducing readmissions and mortality in patients with CAD. METHODS: We systematically searched English language studies from January 1, 2007, to August 3, 2021, in multiple databases. Studies comparing mHealth-enabled DMPs with standard DMPs without mHealth were included if they had a minimum 30-day follow-up for at least one of all-cause or cardiovascular-related mortality, readmissions, or major adverse cardiovascular events. RESULTS: Of the 3,411 references from our search, 155 full-text studies were assessed for eligibility, and data were extracted from 18 publications. Pooled findings for all-cause readmissions (10 studies, n ¼ 1,514) and cardiac-related readmissions (9 studies, n ¼ 1,009) indicated that mHealth-enabled DMPs reduced all-cause (RR: 0.68; 95% CI: 0.50- 0.91) and cardiac-related hospitalizations (RR: 0.55; 95% CI: 0.44-0.68) and emergency department visits (RR: 0.37; 95% CI: 0.26-0.54) compared to DMPs without mHealth. There was no significant reduction for mortality outcomes (RR: 1.72; 95% CI: 0.64-4.64) or major adverse cardiovascular events (RR: 0.68; 95% CI: 0.40-1.15). CONCLUSIONS: DMPs integrated with mHealth should be considered an effective intervention for better outcomes in patients with CAD.
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    Screening for Coronary Artery Disease in Cancer Survivors JACC: CardioOncology State-of-the-Art Review
    Velusamy, R ; Nolan, M ; Murphy, A ; Thavendiranathan, P ; Marwick, TH (ELSEVIER, 2023-02)
    Coronary artery disease (CAD) is an important contributor to the cardiovascular burden in cancer survivors. This review identifies features that could help guide decisions about the benefit of screening to assess the risk or presence of subclinical CAD. Screening may be appropriate in selected survivors based on risk factors and inflammatory burden. In cancer survivors who have undergone genetic testing, polygenic risk scores and clonal hematopoiesis markers may become useful CAD risk prediction tools in the future. The type of cancer (especially breast, hematological, gastrointestinal, and genitourinary) and the nature of treatment (radiotherapy, platinum agents, fluorouracil, hormonal therapy, tyrosine kinase inhibitors, endothelial growth factor inhibitors, and immune checkpoint inhibitors) are also important in determining risk. Therapeutic implications of positive screening include lifestyle and atherosclerosis interventions, and in specific instances, revascularization may be indicated.
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    Association of biomarkers and risk scores with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus
    Halabi, A ; Potter, E ; Yang, H ; Wright, L ; Sacre, JW ; Shaw, JE ; Marwick, TH (BMC, 2022-12-09)
    BACKGROUND: Subclinical LV dysfunction (LVD) identifies heart failure (HF) risk in type 2 diabetes mellitus (T2DM). We sought the extent to which clinical scores (ARIC-HF, WATCH-DM), natriuretic peptides (NTpBNP) and troponin (hs-TnT) were associated with subclinical LV dysfunction (LVD). These associations could inform the ability of these tests to identify which patients should undergo echocardiography. METHODS: Participants with T2DM were prospectively recruited from three community-based populations. ARIC-HF risk at 4 years and WATCH-DM scores were calculated from clinical data. NTpBNP and hs-TnT were measured using an electro-chemiluminescence assay. All underwent a comprehensive echocardiogram. We calculated the sensitivity and specificity of clinical scores and biomarkers to identify abnormal global longitudinal strain (GLS ≥ -16%)), diastolic function (E/e' ≥ 14 or e' < 8 cm/s), left atrial volume index (LAV > 34 ml/m2) and LV hypertrophy (LV mass index > 88 g/m2 (F) > 102 g/m2(M)). RESULTS: Of 804 participants (median age 69 years [inter-quartile range (IQR) 65-73], 36% female), clinical scores suggested significant HF risk (median ARIC-HF 8% [IQR 4-12]; WATCH-DM 10 points [IQR 8-12]), and the median NTpBNP was 50 pg/mL [IQR 25-101] and hs-TnT 9.6 pg/mL [IQR 6.8-13.6]. Abnormal GLS was present in 126 (17%), elevated E/e' in 114 (15%), impaired e' in 629 (78%), increased LAV in 351 (44%) and LV hypertrophy in 113 (14%). After adjustments for age, body-mass index, and renal function, each standard deviation increase in NTpBNP was associated with a GLS increase of 0.32 (p < 0.001) and hs-TnT increase by 0.26 (p < 0.001). Similar trends were observed with ARIC-HF (standardised β = 0.22, p < 0.001) and WATCH-DM (standardised β = 0.22, p < 0.001) in univariable analyses. However, none of the risk assessment tools provided satisfactory discrimination for abnormal GLS (AUC 63%), diastolic indices (e' AUC 54-61%) or LV mass (AUC 59-67%). At a sensitivity of 90%, there was an unacceptably low (< 50%) specificity. CONCLUSION: Although risk assessment based on clinical scores or biomarkers would be desirable to stratify HF risk in people with T2DM, they show a weak relationship with subclinical LVD.
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    Application of a risk-guided strategy to secondary prevention of coronary heart disease: analysis from a state-wide data linkage in Queensland, Australia
    Huynh, QL ; Nghiem, S ; Byrnes, J ; Scuffham, PA ; Marwick, T (BMJ PUBLISHING GROUP, 2022-05)
    OBJECTIVE: This study sought whether higher risk patients with coronary heart disease (CHD) benefit more from intensive disease management. DESIGN: Longitudinal cohort study. SETTING: State-wide public hospitals (Queensland, Australia). PARTICIPANTS: This longitudinal study included 20 426 patients hospitalised in 2010 with CHD as the principal diagnosis. Patients were followed-up for 5 years. PRIMARY AND SECONDARY OUTCOMES AND MEASURES: The primary outcome was days alive and out of hospital (DAOH) within 5 years of hospital discharge. Secondary outcomes included all-cause readmission and all-cause mortality. A previously developed and validated risk score (PEGASUS-TIMI54) was used to estimate the risk of secondary events. Data on sociodemography, comorbidity, interventions and medications were also collected. RESULTS: High-risk patients (n=6573, risk score ≥6) had fewer DAOH (∆=-142 days (95% CI: -152 to -131)), and were more likely to readmit or die (all p<0.001) than their low-risk counterparts (n=13 367, risk score <6). Compared with patients who were never prescribed a medication, those who consumed maximal dose of betablockers (∆=39 days (95% CI: 11 to 67)), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (∆=74 days (95% CI: 49 to 99)) or statins (∆=109 days (95% CI: 90 to 128)) had significantly greater DAOH. Patients who received percutaneous coronary intervention (∆=99 days (95% CI: 81 to 116)) or coronary artery bypass grafting (∆=120 days (95% CI: 92 to 148)) also had significantly greater DAOH than those who did not. The effect sizes of these therapies were significantly greater in high-risk patients, compared with low-risk patients (interaction p<0.001). Analysis of secondary outcomes also found significant interaction between both medical and interventional therapies with readmission and death, implicating greater benefits for high-risk patients. CONCLUSIONS: CHD patients can be effectively risk-stratified, and use of this information for a risk-guided strategy to prioritise high-risk patients may maximise benefits from additional resources spent on intensive disease management.
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    Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF).
    McMurray, JJV ; Anand, IS ; Diaz, R ; Maggioni, AP ; O'Connor, C ; Pfeffer, MA ; Solomon, SD ; Tendera, M ; van Veldhuisen, DJ ; Albizem, M ; Cheng, S ; Scarlata, D ; Swedberg, K ; Young, JB ; RED-HF Committees Investigators, (Wiley, 2013-03)
    AIMS: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. METHODS AND RESULTS: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. CONCLUSION: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
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    Clinical, Echocardiographic, and Biomarker Associations With Impaired Cardiorespiratory Fitness Early After HER2-Targeted Breast Cancer Therapy
    Bonsignore, A ; Marwick, TH ; Adams, SC ; Thampinathan, B ; Somerset, E ; Amir, E ; Walker, M ; Abdel-Qadir, H ; Koch, CA ; Ross, HJ ; Woo, A ; Wintersperger, BJ ; Haykowsky, MJ ; Thavendiranathan, P (ELSEVIER, 2021-12)
    BACKGROUND: Cardiorespiratory fitness (CRF) is reduced in cancer survivors and predicts cardiovascular disease (CVD)-related and all-cause mortality. However, routine measurement of CRF is not always feasible. OBJECTIVES: The purpose of this study was to identify clinical, cardiac biomarker, and imaging measures associated with reduced peak oxygen consumption (VO2peak) (measure of CRF) early post-breast cancer therapy to help inform CVD risk. METHODS: Consecutive women with early-stage HER2+ breast cancer receiving anthracyclines and trastuzumab were recruited prospectively. Within 6 ± 2 weeks of trastuzumab completion, we collected clinical information, systolic/diastolic echocardiographic measures, high-sensitivity troponin I, B-type natriuretic peptide, and VO2peak using a cycle ergometer. Regression models were used to examine the association between VO2peak and clinical, imaging, and cardiac biomarkers individually and in combination. RESULTS: Among 147 patients (age 52.2 ± 9.3 years), the mean VO2peak was 19.1 ± 5.0 mL O2·kg-1·min-1 (84.2% ± 18.7% of predicted); 44% had a VO2peak below threshold for functional independence (<18 mL O2·kg-1·min-1). In multivariable analysis, absolute global longitudinal strain (GLS) (β = 0.58; P = 0.007), age per 10 years (β: -1.61; P = 0.001), and E/e' (measure of diastolic filling pressures) (β = -0.45; P = 0.038) were associated with VO2peak. GLS added incremental value in explaining the variability in VO2peak. The combination of age ≥50 years, E/e' ≥7.8, and GLS <18% identified a high probability (85.7%) of compromised functional independence, whereas age <50 years, E/e' <7.8, and GLS ≥18% identified a low probability (0%). High-sensitivity troponin I and B-type natriuretic peptide were not associated with VO2peak. CONCLUSIONS: Readily available clinical measures were associated with VO2peak early post-breast cancer therapy. A combination of these parameters had good discrimination to identify patients with compromised functional independence and potentially increased future CVD risk.
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    Cost-Effectiveness of Obstructive Sleep Apnea Screening and Treatment Before Catheter Ablation for Symptomatic Atrial Fibrillation.
    Kawakami, H ; Saito, M ; Kodera, S ; Fujii, A ; Nagai, T ; Uetani, T ; Tanno, S ; Oka, Y ; Ikeda, S ; Komuro, I ; Marwick, TH ; Yamaguchi, O (Japanese Circulation Society, 2020-08-27)
    Background: Although management of obstructive sleep apnea (OSA) has been recommended to improve outcomes of catheter ablation (CA) in patients with symptomatic atrial fibrillation (AF), the most cost-effective way of preprocedural OSA screening is undetermined. This study assessed the cost-effectiveness of OSA management before CA for symptomatic AF. Methods and Results: A Markov model was developed to assess the cost-effectiveness of 3 OSA detection strategies before CA: no screening; Type 3 portable monitor (PM)-guided screening; and polysomnography (PSG)-guided screening. The target population consisted of a hypothetical cohort of patients aged 65 years with symptomatic AF, with 50% prevalence of OSA. We used a 5-year horizon, with sensitivity analyses for significant variables and scenario analyses for lower and higher OSA prevalence (30% and 70%, respectively). In the base-case, both types of OSA screening were dominant (less costly and more effective) relative to no screening. Although PSG-guided management was more effective than PM-guided management, it was more costly and therefore did not show clear benefit. These findings were replicated in cohorts with lower and higher OSA risks. Conclusions: OSA screening before CA is cost-effective in patients with symptomatic AF, with PM screening being the most cost-effective. Physicians should consider OSA management using this simple tool in the decision making for treatment of symptomatic AF.
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    Oral and intravenous glucose administration elicit opposing microvascular blood flow responses in skeletal muscle of healthy people: role of incretins
    Roberts-Thomson, KM ; Parker, L ; Betik, AC ; Wadley, GD ; Della Gatta, PA ; Marwick, TH ; Keske, MA (WILEY, 2022-04)
    Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut-derived hormones that may explain these divergent responses. Ten healthy individuals underwent a 120 min oral glucose tolerance test (OGTT; 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast-enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C-peptide, glucagon, non-esterified fatty acids and a range of gut-derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(GLP-1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3-fold versus 0.5-fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8-fold higher plasma insulin concentrations (P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations (r = -0.665, P < 0.0001). The natural log ratio of incretins GLP-1:GIP was positively associated with ΔMBF (r = 0.658, P < 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. KEY POINTS: Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients; however, this vascular effect is lost during insulin resistance. Food/drinks containing large glucose loads impair MBF in healthy people; however, this impairment is not observed when glucose is infused intravenously (bypassing the gut). We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose-mediated changes in MBF. Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin-mediated MBF response to oral glucose ingestion. This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction.
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    Global Longitudinal Strain Monitoring to Guide Cardioprotective Medications During Anthracycline Treatment
    Marwick, TH (SPRINGER, 2022-06)
    PURPOSE OF THE REVIEW: Anthracycline chemotherapy carries a risk of myocardial dysfunction and heart failure even at relatively low doses, and the clinical prediction of cancer treatment-related cardiac dysfunction (CTRCD) is inexact. Careful imaging or biomarker surveillance during chemotherapy can identify CTRCD before the development of heart failure. Currently, this surveillance is performed using ejection fraction (EF). While this is a reliable and reproducible test with three-dimensional techniques, the most widely used imaging technique is two-dimensional echocardiography, for which EF measurements have broad confidence intervals. RECENT FINDINGS: The use of global myocardial strain (GLS) provides a more reliable and reproducible means of assessing global cardiac function and shows meaningful changes before a significant change of EF. Observational studies have shown that although absolute measurements of GLS, both at baseline and during therapy, are predictive of CTRCD risk, the most reliable approach is to assess the change of GLS with therapy - a meaningful relative change of 10-15% being significant. A clinical trial comparing GLS to EF surveillance did not show a significant change of EF in the overall study group, but did show that patients managed with a the GLS-guided approach were less likely to develop a meaningful change of cardiac function to an abnormal level. In at-risk patients, there is good evidence for the protective value of neurohormonal antagonists and statins: the use of GLS enables these benefits to be directed to those most likely to benefit, while minimizing their use in the majority of people, who do not need them. Although GLS requires an element of training and efforts to ensure uniformity, it has proven to be a feasible, robust, and reproducible technique, ready for wide adoption.